This proposal is a supplement designed to expand our ongoing, Phase II, placebo-controlled clinical trial (NS050597, "Androgen effect on motor/cognitive outcome in Klinefelter syndrome" [KS]). We are currently investigating the impact of androgen replacement for 24 months on motor function and aspects of cognition in boys with KS ages 4-12 years. The Primary aim of this supplement is to investigate how androgen replacement therapy affects brain structure and function in an androgen-deficient population, boys with KS, in the context of a unique ongoing clinical trial. This proposed study will investigate the structural and functional brain differences between boys with KS (8-12 years) and age-matched control boys and will longitudinally examine brain morphometry and function associated with androgen replacement in KS. KS is a genetic disorder that occurs in 1/500-1000 males and is defined by the karyotype 47,XXY. The KS neurocognitive phenotype includes impaired motor function, language-based learning difficulties, and executive function (attention/working memory) deficits. The ongoing randomized, placebo-controlled clinical trial attempts to restore normal testosterone levels in boys with KS, ages 4-12 years, through treatment with androgen (oxandrolone) for 2 years. Specific Aim #1 (in the ongoing clinical trial) predicts improved performance in androgen-treated compared to placebo-treated boys with KS in several aspects of motor function. Specific Aim #2 (in the ongoing clinical trial) predicts improved performance in androgen-treated compared to placebo-treated boys with KS in selected aspects of cognition, specifically in language and executive function. Boys with KS have smaller brain volumes in regions related to language, memory retrieval and working memory, and motor function including the fronto-parietal regions (related to working memory), frontal, parieto-temporal regions (related to language) and motor regions (related to motor function), compared to control boys. Structure and function in these specific areas have been shown to change in response to androgen replacement. Most importantly, changes in these regions have been associated with changes in the cognitive functions that we have hypothesized will improve with androgen replacement in the ongoing Phase II clinical trial. In this supplement, we will use structural and functional MRI (fMRI) protocols to 1) compare brain structure and function in boys with KS with age-matched control boys and 2) study the effects of androgen replacement on brain structure and function in androgen- versus placebo-treated boys with KS (ongoing clinical trial). This supplement represents a unique opportunity to assess changes in the KS brain longitudinally during this interval of androgen replacement and will add to the significance of the ongoing clinical trial by increasing our knowledge of brain structure and function in KS. We aim to link the structural and functional neuroimaging findings of androgen deficiency and replacement in KS, in order to expand our understanding of mechanisms underlying androgen impact on cognition. PUBLIC HEALTH RELEVANCE: The structural and functional brain imaging in this supplement will provide unique insight into the role of androgen in male brain development and will significantly expand the ongoing clinical trial ("Androgen effect on motor/cognitive outcome in Klinefelter syndrome"). Our goals are to 1) help define the differences in brain structure and function that distinguish boys with Klinefelter syndrome from control boys and 2) provide insights into the brain changes associated with improved cognitive function in androgen-treated KS subjects. We aim to link the structural and functional neuroimaging findings of androgen deficiency and replacement in KS, in order to expand our understanding of mechanisms underlying androgen impact on cognition.